Luteolin, an aryl hydrocarbon receptor ligand, suppresses tumor metastasisin vitroandin vivo

Estrogen receptor (ER)-negative breast tumors are associated with low survival rates, which is related to their ability to grow and metastasize into distal organs. The aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor that is involved in several biological processes, is a promising anti-metastatic target. Luteolin, a non-toxic naturally occurring plant flavonoid with diverse biological activities, has been demonstrated to be effective against certain types of cancer, and has also been described as a ligand of AhR. In the present study, various cancer cell lines were first investigated following treatment with luteolin, and luteolin exhibited the lowest IC(50)in MDA-MB-231 cells. Then, the efficiency of luteolin in suppressing the metastasis of ER-negative breast cancerin vitrowas assessed. MDA-MB-231 cells were treated with luteolinin vitro. Subsequently, MTT assay and flow cytometry were used to detect cell viability, the cell cycle and apoptosis, and a Transwell assay was used to evaluate cell invasion. In addition, reverse transcription-semi-quantitative PCR and western blot were performed to detect the mRNA and protein expression levels of matrix metalloproteinase (MMP)-2 and MMP-9. In addition, the number of surface tumor nodules was measuredin vivo, in mice bearing B16-F10 tumors, following treatment with luteolin. Luteolin inhibited the viability and induced the apoptosis of MDA-MB-231 cells, which was accompanied by cell cycle arrest. This was associated with a decrease in the expression of the pro-metastatic markers C-X-C chemokine receptor type 4 (CXCR4), MMP-2 and MMP-9, which was reversed by AhR inhibition. Furthermore, it was identified that luteolin could inhibit the metastasis in a B16F10 mouse xenograft model, and the levels of MMP-9, MMP-2 and CXCR4 were significantly decreased in the lung tissues isolated from tumor-bearing nude mice following luteolin treatment. In conclusion, luteolin is a potential molecule for inhibiting breast cancer invasion and metastasis, which could have promising clinical applications.